High morbidity in adults with non-transfusion-dependent thalassemia referred to u.S. specialty centers

Abstract Introduction Non-transfusion-dependent thalassemia (NTDT) is a clinically significant form of thalassemia associated with progressive morbidity. Many patients are referred to specialty centers only after complications have developed, reflecting gaps in recognition and management of thalassemia in community settings. We aimed to characterize clinical features of adults with NTDT at the time of referral to U.S. thalassemia centers to identify opportunities for earlier intervention. Methods We performed a multicenter cross-sectional study of adult patients with NTDT referred to 1 of 3 thalassemia centers of excellence in the U.S. between 2013 and 2023. The thalassemia centers included in this study are the Penn Comprehensive Adult Thalassemia Program, the Northern California Comprehensive Thalassemia Center, and the Weill Cornell Medicine Comprehensive Thalassemia Center. We included patients age 18 at the time of referral who had a clinical diagnosis of NTDT. Each patient's chart was manually reviewed by the study authors. Demographics, genotype, lab values, organ-specific complications, and transfusion history were abstracted from medical records. Finally, a separate variable was recorded for whether the patient was ultimately transitioned to a regular transfusion regimen. Results 82 adults with NTDT were identified: 45% with α-thalassemia (deletional and non-deletional HbH disease) and 55% with β-thalassemia syndromes. The median age at referral was 36.5 years (range 18-74); 66% were female. Splenectomy was reported in 53% of β-thalassemia patients versus 11% of α-thalassemia patients. Pulmonary hypertension (14% vs. 3%, p=0.08) and paraspinal masses (29% vs. 5.5%, p=0.04) were more common in β-thalassemia. Arrhythmias occurred in 9% of β-thalassemia patients and none with α-thalassemia. Decreased bone mineral density was the most common endocrinopathy (43% in α-thalassemia and 34% in β-thalassemia). A history of venous thromboembolism was reported in 13% of β-thalassemia patients, and none in α-thalassemia. Baseline hemoglobin was lower among β-thalassemia patients (median 8.6 g/dL) compared to those with α-thalassemia (median 9.5 g/dL, p=0.03). Serum ferritin was significantly higher in those with β-thalassemia (median 766.5 ng/mL) versus α-thalassemia (median 419.7 ng/mL, p=0.002). 38% of patients had ferritin levels 800 ng/mL, exceeding the Thalassemia International Federation (TIF) NTDT guideline threshold for initiating iron overload evaluation and treatment; of these, only 22.6% were on iron chelation at the time of first thalassemia evaluation. Of the 71% of patients with a liver iron concentration above 5 mg iron/g dry liver weight on initial evaluation, only 15% were on iron chelation. Among those with cardiac MRI performed at the time of evaluation, three individuals had a cardiac T2* less than 20 milliseconds, and none of these individuals were on iron chelation prior to referral to the thalassemia center. Overall, despite a diagnosis of NTDT at the time of referral, 49% of patients (n=40) were ultimately recommended to initiate regular transfusion therapy following evaluation at a thalassemia center. Among the 37 patients with documented reasons for starting transfusions, 49% began transfusions due to symptomatic anemia or fatigue, 40% due to extramedullary hematopoiesis or ineffective erythropoiesis, 16% due to pulmonary hypertension, heart failure, or cardiopulmonary symptoms, and 5% due to pregnancy. Six patients (16%) had more than one documented indication. Conclusion This is the first multicenter epidemiologic analysis specifically focused on adult patients with NTDT in the United States. We observed a substantial burden of disease and late-stage complications of thalassemia at the time of first hematology evaluation. Nearly half of all patients were ultimately initiated on chronic transfusion therapy, despite a prior NTDT designation. Patients exhibited a high prevalence of complications related to chronic ineffective erythropoiesis and iron overload, particularly among those with β-thalassemia syndromes. Our findings support the emerging evidence that many people with NTDT only present to thalassemia specialty centers after the onset of potentially irreversible complications, and that people with thalassemia may have transfusion requirements that evolve over time. Initiatives to better disseminate thalassemia guidelines and define referral criteria are urgently needed.